Spinal cord stimulation (SCS) is an implanted medical device therapy for refractory chronic pain. However, fewer than 2/3 of patients typically experience at least a 50% reduction in pain, and despite several decades of research and development, the proportion of patients achieving clinical success has not increased over time. We are pursuing a new stimulation parameter dimension ? the temporal pattern of stimulation ? and the purpose of this project is to design and test optimized temporal patterns of stimulation to improve the efficacy of SCS to treat chronic neuropathic pain. We will use a validated biophysically-based model of the effects of SCS on sensory signal processing in the dorsal horn of the spinal cord to design optimized temporal patterns of SCS. The optimized temporal patterns are intended to exploit the dynamics of inhibitory mechanisms in the dorsal horn of the spinal cord. SCS produces both excitation and inhibition of pain transmitting spinal neurons, and the temporal patterns will be optimized to weaken SCS-mediated excitation while amplifying SCS-mediated inhibition. We will use sensitivity analyses to determine the robustness of stimulation patterns to potential variations in electrode positioning, selectivity of stimulation, and the biophysical properties of the dorsal horn neural network, especially the compromised inhibitory mechanisms present in chronic pain. Subsequently, we will measure the effects of the temporal pattern of SCS on pain-related behavioral outcomes in the spared nerve injury (SNI) rat model of chronic neuropathic pain. We expect that novel temporal patterns of SCS will produce greater suppression of allodynia and hyperalgesia, as well as spontaneous pain, than will frequency-matched control patterns. Our in silico and in vivo electrophysiological data demonstrate that temporal patterns of SCS produced a more than 50% greater suppression of projection neuron firing rates than conventional SCS, and this suggests that resulting improvements in in pain outcomes will exceed the 30% threshold for meaningful change. We will also quantify the effects of optimized temporal pattern of SCS on the activity of spinal cord projection neurons in the SNI rat model of chronic pain. We expect that optimized temporal patterns of SCS will produce greater reductions in firing rates and wind up of spinal wide dynamic range and nociceptive specific neurons than frequency matched control patterns. The temporal pattern of SCS is a novel and important parameter that we will exploit to expand the design space for SCS from the spatial distribution?where?of stimulation to the temporal pattern?when?of stimulation. The outcome will be an assessment of the feasibility of using optimized temporal patterns of SCS to treat neuropathic pain, and will provide the foundation for translational studies in patients with chronic pain. Importantly, this approach has a clear and comparatively short road to clinical translation, as existing implanted pulse generators could be re-programmed to deliver optimized temporal patterns of SCS.